Abstract

Background

Group I metabotropic glutamate receptors (mGluR) are coupled via Gαq/11 to the activation of phospholipase Cβ, which hydrolyzes membrane phospholipids to
form inositol 1,4,5 trisphosphate and diacylglycerol. In addition to functioning as
neurotransmitter receptors to modulate synaptic activity, pathological mGluR5 signaling
has been implicated in a number of disease processes including Fragile X, amyotrophic
lateral sclerosis, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s
disease, epilepsy, and drug addiction. The expression of mGluR5 in astrocytes has
been shown to be increased in several acute and chronic neurodegenerative conditions,
but little is known about the functional relevance of mGluR5 up-regulation in astrocytes
following injury.

Results

In the current study, we investigated primary mouse cortical astrocyte cell death
in response to oxygen glucose deprivation (OGD) and found that OGD induced both necrotic
and apoptotic cell death of astrocytes. OGD resulted in an increase in astrocytic
mGluR5 protein expression, inositol phosphate formation and extracellular regulated
kinase (ERK1/2) phosphorylation, but only inositol phosphate formation was blocked
with the mGluR5 selective antagonist MPEP. Cortical astrocytes derived from mGluR5
knockout mice exhibited resistance to OGD-stimulated apoptosis, but a lack of mGluR5
expression did not confer protection against necrotic cell death. The antagonism of
the inositol 1,4,5 trisphosphate receptor also reduced apoptotic cell death in wild-type
astrocytes, but did not provide any additional protection to astrocytes derived from
mGluR5 null mice. Moreover, the disruption of Homer protein interactions with mGluR5
also reduced astrocyte apoptosis.

Conclusion

Taken together these observations indicated that mGluR5 up-regulation contributed
selectively to the apoptosis of astrocytes via the activation of phospholipase C and
the release of calcium from intracellular stores as well as via the association with
Homer proteins.